CN113330017B - Purification method and application of SGLTs inhibitor - Google Patents
Purification method and application of SGLTs inhibitor Download PDFInfo
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- CN113330017B CN113330017B CN202080009907.8A CN202080009907A CN113330017B CN 113330017 B CN113330017 B CN 113330017B CN 202080009907 A CN202080009907 A CN 202080009907A CN 113330017 B CN113330017 B CN 113330017B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
Abstract
A method for purifying SGLTs inhibitor and its application are provided. The SGLTs inhibitor is (1S, 2S,3S,4R, 5S) -5- (3- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) methyl) -4-ethylphenyl) -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol. Reacting p-nitrobenzoic acid or a derivative thereof with a compound of a formula (A), and hydrolyzing to obtain a high-purity compound; the invention also discloses a diethylamine solvate obtained by further reacting the purified compound, and the diethylamine solvate is expected to be developed into a new generation SGLTs inhibitor.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a purification method and application of an SGLTs inhibitor.
Background
Diabetes is a metabolic disorder, recurrent or persistent hyperglycemia. Diet and exercise therapy are the preferred glycemic control regimens in the early stages of diabetes treatment. When these methods are difficult to achieve blood glucose control, treatment with insulin or oral hypoglycemic drugs is required. It has been found that the regulation of glucose transport processes by cells is mainly achieved by two protein family members, glucose transporters (GLUTs) (passive transport) and sodium-dependent glucose co-transporters (SGLTs) (active transport). The SGLTs family members with glucose transport functions are mainly distributed in the proximal tubules and other parts of intestines and kidneys, and further are inferred to play a key role in processes of intestinal glucose absorption, renal glucose reuptake and the like, so that the SGLTs family members become one of ideal potential targets for treating diabetes. In conclusion, the SGLTs inhibitor has a good development prospect as a novel diabetes treatment drug. Therefore, there is an urgent need to develop a compound with good therapeutic effect, pharmacological property and safety for treating diabetes and related metabolic disorders.
In 2015, the pharmaceutical group ltd of heuson, jiangsu, in patent application WO2015/032272A1, discloses a series of compounds with inhibitory activity against sodium-dependent glucose co-transporters (SGLTs), the most representative of which compounds of formula (a) have the following structure:
the chemical name is as follows: (1S, 2S,3S,4R, 5S) -5- (3- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) methyl) -4-ethylphenyl) -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol has very obvious inhibition effect on SGLT2 and SGLT1, and is expected to be developed into a single SGLT2 inhibitor or a dual SGLT2/SGLT1 inhibitor. However, in view of the structural characteristics of these compounds and the fact that they contain a large amount of impurities and are generally oily or foamy solids, patent application WO2015/032272A1, example 9, discloses an amorphous compound of formula (a) which contains a large amount of impurities and is difficult to remove in subsequent developments. Therefore, there is an urgent need to develop a method for purifying the compound of formula (a) for industrial production and to prepare an API that is acceptable to meet the needs of clinical research and the production of pharmaceutical preparations on the market.
Disclosure of Invention
The invention aims to provide a purification method of SGLTs inhibitor, thereby meeting the requirements of clinical research and production of pharmaceutical preparations on the market.
In a first aspect, the present invention provides a process for the purification of a compound of formula (a) comprising the steps of:
step 1), reacting a compound shown in a formula (A) to generate a compound shown in a formula (B);
step 2) hydrolyzing the compound shown in the formula (B) to generate the compound shown in the formula (A), wherein the reaction route is as follows:
preferably, in the purification method, the compound of formula (a) in step 1) is reacted with p-nitrobenzoic acid or a derivative thereof to produce the compound of formula (B).
As a further preferable mode, in the purification method, the p-nitrobenzoic acid derivative in step 1) is p-nitrobenzoyl chloride, p-nitrobenzoyl chloride or p-nitrobenzoic anhydride.
As a further preferable scheme, in the purification method, the feeding molar ratio of the compound in the formula (A) in the step 1) to the p-nitrobenzoic acid is 1.0 to (1.0-6.0).
As a further preferable scheme, in the purification method, the feeding molar ratio of the compound in the formula (A) in the step 1) to the p-nitrobenzoic acid is 1.0 to (3.0-4.0).
As a further preferred variant, the molar ratio of compound of formula (A) to p-nitrobenzoic acid fed in step 1) in the purification process is 1.0:4.0.
Preferably, the organic layer is washed with sodium bicarbonate during the treatment after the reaction of step 1) and/or step 2) in the purification method. The excess or generated p-nitrobenzoic acid or the derivative thereof can be removed as far as possible by adding sodium bicarbonate solution for washing in the step 1) and/or the step 2).
Preferably, the purification method comprises the step of purifying the product of the compound of formula (B) obtained in step 1) with acetonitrile, isopropanol, dichloromethane or a mixture thereof.
As a further preferred scheme, after the compound product of the formula (B) is obtained in the step 1) in the purification method, acetonitrile and/or isopropanol are used for purification.
As a further preferred scheme, the purification method is carried out by using dichloromethane after the compound product of the formula (B) is obtained in the step 1).
In a second aspect, the present invention provides an intermediate compound of formula (B) in a process for purifying a compound of formula (a), having the structure:
in a third aspect, the present invention provides a process for the preparation of a compound of formula (I) comprising the steps of:
step 1) contacting the compound of formula (A) prepared by the purification method with diethylamine;
step 2) adding seed crystals and/or an anti-solvent until the solution is turbid or a combination thereof, and continuing crystallization;
and 3) carrying out solid-liquid separation to obtain a compound shown in the formula (I), wherein the reaction route is as follows:
preferably, in the method for preparing the compound of formula (I), the diethylamine in step 1) is pure liquid diethylamine, an aqueous solution of diethylamine, or a mixture of diethylamine and an organic solvent.
Preferably, in the preparation method of the compound of the formula (I), the compound of the formula (A) is dissolved in diethylamine in the step 1) or the compound of the formula (A) is dissolved in an organic solvent firstly, and then the diethylamine is added.
Preferably, in step 2) of the method for preparing the compound of formula (I), the antisolvent is selected from the group consisting of water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, diethyl ether, and mixtures thereof.
As a preferable mode, in the method for preparing the compound of formula (I), the organic solvent is selected from the group consisting of methanol, ethanol, N-propanol, isopropanol, N-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, benzene, toluene, xylene, and a mixture thereof.
As a further preferable scheme, in the preparation method of the compound of the formula (I), after the solid-liquid separation in step 3), a step of further drying is included to obtain the compound of the formula (I), and the drying process specifically includes drying at room temperature, and then drying at a controlled temperature of 30 to 60 ℃, preferably at 35 to 45 ℃.
Compared with the prior art, the invention has the following technical advantages:
1. the invention is an industrialized purification method, which solves the problem of drug accessibility.
2. The invention has simple raw materials or reagents, mild reaction conditions and strong operability.
3. The invention develops a key intermediate compound shown as the formula (B), which has stable physicochemical property and is not easy to degrade.
4. The purity of the compound of the formula (B) can be improved by adding a recrystallization step in the step 1) of the purification method, so that the purity of the compound of the formula (I) can be improved, and the appearance of the product is improved.
5. The invention changes the drying method of the compound shown in the formula (I) to obtain a product suitable for clinical application, and all indexes such as water, solvent residue, burning residue and the like meet the clinical requirements.
Detailed Description
The present inventors have extensively and intensively studied and, for the first time, developed a method for purifying SGLTs inhibitors having a structure of the compound of formula (a). The invention adopts p-nitrobenzoic acid or derivatives thereof to react the compound of the formula (A), and the high-purity compound of the formula (A) is obtained through post-treatment. Further, the purified compound of the formula (a) is reacted to obtain a diethylamine solvate (compound of the formula (I)), and the diethylamine solvate can be widely applied to the treatment or delay of diseases such as diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis or hypertension, and is expected to be developed into a new-generation SGLTs inhibitor. On the basis of this, the present invention has been completed.
The present invention will be described more fully hereinafter with reference to the accompanying examples, but the present invention is not limited thereto, and is not limited thereto.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker BioSpin Gmbh 600 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) And deuterated acetone ((CD) 3 ) 2 CO) with internal standard Tetramethylsilane (TMS).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification adopted by TLC is 0.15 mm-0.20 mm.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out in a dry nitrogen or argon atmosphere, without specific mention, as a dry solvent, and the reaction temperature is in degrees centigrade (. Degree. C.).
Example 1
12.64kg of tetrahydrofuran was charged into the reaction vessel, and 2.83kg (6.37 mol) of the oily compound of formula (A), 4.11Kg of N, N-Diisopropylethylamine (DIPEA) and 0.387kg of 4-Dimethylaminopyridine (DMAP) were successively added thereto with stirring at room temperature. Cooling the reaction system to below 15 ℃, adding 4.72kg (25.44 mol) of paranitrobenzoyl chloride into 12.64kg of tetrahydrofuran, stirring and dissolving until the mixture is clear, dropwise adding the clear solution into the reaction system of the reaction kettle, and controlling the temperature to be 15-40 ℃ in the dropwise adding process. After the dropwise addition, the temperature is raised to 45-50 ℃, the mixture is kept warm and stirred for reaction for about 3.5 hours, and the TLC detection reaction is finished. 28.29kg of water and 12.26kg of ethyl acetate were added, and the mixture was stirred, left to stand and layered, and an organic layer and an aqueous layer were collected, respectively. The aqueous layer was extracted with 12.26kg of ethyl acetate, and the organic layer was collected. All organic layers were combined, 14.14kg x 2 of 8% sodium bicarbonate solution was added, stirred and left to separate layers, and the organic layers were collected, dried by adding anhydrous sodium sulfate. Filtration, washing of the filter cake with ethyl acetate and concentration of the filtrate to dryness gave the compound of formula (B) as an oil.
To the oily compound of formula (B) obtained above was added 8.96kg of acetonitrile, and the mixture was dissolved with stirring, followed by addition of 13.39kg of isopropyl alcohol. Heating to reflux and dissolve, stirring at 75-80 deg.c for 10-15 min, cooling to 15-25 deg.c and stirring for 3 hr. Filtration was carried out, and the filter cake was washed once with a mixed solvent (2.26 kg of acetonitrile and 3.39kg of isopropyl alcohol), and then, dried by suction.
The dried product was added to 30.08kg of methylene chloride, dissolved with stirring, filtered and eluted with 37.63kg of methylene chloride. The filtrate was concentrated to dryness to give 2.17kg (yield 32.7%) of the compound of formula (B) as a product.
1 HNMR(400MHz，DMSO-d 6 )δ8.34(d，2H)，δ8.21(m，10H)，δ7.93(dd，4H)，δ7.42(d，1H)，δ7.39(s，1H)，δ7.19(d，1H)，δ6.46(d，1H)，δ6.25(t，2H)，δ6.19(m，1H)，δ6.00(s，2H)，δ5.01(d，1H)，δ4.80(d，1H)，δ4.64(d，1H)，δ4.13(d，1H)，δ4.09(s，4H)，δ3.79(s，2H)，δ2.38(q，2H)，δ0.93(t，3H).
Example 2
2.16kg of the compound of formula (B) was charged into a reaction vessel, 8.64kg of acetonitrile was added, heated to reflux, and dissolved with stirring. Slowly dripping 8.64kg of isopropanol, slowly cooling to 20-25 ℃ after dripping, continuously stirring for 1.5 hours at controlled temperature, filtering, washing a filter cake once with a mixed solvent (acetonitrile and isopropanol), pumping, and drying the filter cake to obtain 2.12kg of a yellow solid compound of the formula (B) (the yield is 98.15%, and the purity is 99.3%).
Example 3
2.80kg (2.69 mol) of the compound of formula (B) are introduced into a reaction vessel, 11.95kg of tetrahydrofuran are added and stirred until clear. 0.565kg (13.46 mol) of lithium hydroxide monohydrate was added to 13.45kg of water and stirred until clear. And (3) adding the lithium hydroxide solution into a reaction system of a reaction kettle at the temperature of between 20 and 30 ℃, stirring and reacting for 3 hours at controlled temperature, and detecting by TLC to finish the reaction. Concentrating the reaction solution to remove tetrahydrofuran, adding 16.02kg of dichloromethane into the residual material, stirring, standing and layering, respectively collecting an organic layer and a water layer, adding 16.02kg of dichloromethane into the water layer for extraction, stirring, standing and layering, and collecting the organic layer. The organic layers were combined, concentrated to dryness, and to the residue were added 10.83kg of ethyl acetate, followed by addition of 6.2kg of 4 of 7.6% sodium bicarbonate solution, followed by stirring, standing for separation, collection of the organic layer, drying with anhydrous sodium sulfate, filtration, and washing of the cake with 1.40kg of ethyl acetate once. 6.72kg of absolute ethanol was added to the above filtrate, and the mixture was concentrated under reduced pressure to dryness to obtain 1.24kg of a solid compound of formula (A) (yield 100%, purity 99.0%).
Example 4
1.2kg (2.70 mol) of the compound of formula (A) was added to 4.28kg of diethylamine, and dissolved by stirring. And (3) filter-pressing the solution into a reaction kettle, dropwise adding water into the reaction solution at the temperature of 20-30 ℃, stopping dropwise adding until the reaction solution is turbid, wherein the dropwise adding water amount is 25.6kg. 1.2g of seed crystal (form I) of the compound of the formula (I) is added, and the temperature-controlled stirring and crystallization are continued for 24 hours. Filtration was carried out and the filter cake was washed once with 5.64kg of a 14.9% aqueous diethylamine solution. The filter cake was dried under vacuum at room temperature for 24 hours and then warmed to 35-40 ℃ for 24 hours to give 1.12kg (yield 80.2%) of the compound of formula (I) as a white powder.
1 HNMR(400MHz，(CD 3 ) 2 CO)δ7.37(m，2H)，δ7.17(d，1H)，δ6.71(d，1H)，δ6.62(m，2H)，δ4.18(s，4H)，δ4.15(d，1H)，δ3.92(s，2H)，δ3.85(m，2H)，δ3.73(m，2H)，δ3.64(d，1H)，δ3.59(d，1H)，δ2.60(q，2H)，δ2.56(q，3H)，δ1.11(t，3H)，δ1.03(t，5H).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (11)
1. A method for purifying a compound of formula (a), comprising the steps of:
step 1), reacting a compound shown in a formula (A) to generate a compound shown in a formula (B);
step 2) hydrolyzing the compound shown in the formula (B) to generate the compound shown in the formula (A), wherein the reaction route is as follows:
the compound in the formula (A) in the step 1) reacts with p-nitrobenzoic acid or a derivative thereof to generate a compound in a formula (B), wherein the feeding molar ratio of the compound in the formula (A) to the p-nitrobenzoic acid or the derivative thereof is 1.0: (1.0-6.0);
washing the organic layer with sodium bicarbonate in the treatment process after the reaction in the step 1) and/or the step 2);
the p-nitrobenzoic acid derivative is p-nitrobenzoyl chloride or p-nitrobenzoic anhydride.
2. The purification process according to claim 1, wherein the molar ratio of the compound of formula (a) to p-nitrobenzoic acid or a derivative thereof is 1.0: (3.0-4.0).
3. The purification process according to claim 1, wherein the molar ratio of the compound of formula (a) to p-nitrobenzoic acid or a derivative thereof is 1.0:4.0.
4. the purification process of claim 1, wherein the product of formula (B) obtained in step 1) is purified with acetonitrile, isopropanol, dichloromethane or a mixture thereof.
5. The purification process according to claim 4, wherein the compound of formula (B) obtained in step 1) is purified with acetonitrile and/or isopropanol.
6. The purification method according to claim 4, wherein the compound of formula (B) obtained in step 1) is purified with dichloromethane.
7. A compound of formula (B):
8. a process for the preparation of a compound of formula (I), comprising the steps of:
step 1) preparing a compound of formula (a) by the purification method of claim 1, contacting the compound of formula (a) with diethylamine;
step 2) adding seed crystals and/or an anti-solvent until the solution is turbid or a combination thereof, and continuing crystallization;
and 3) carrying out solid-liquid separation to obtain a compound shown in the formula (I), wherein the reaction route is as follows:
9. the process for the preparation of the compound of formula (I) according to claim 8, characterized in that the anti-solvent in step 2) is selected from water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, diethyl ether and mixtures thereof.
10. The method for preparing the compound of formula (I) according to claim 8, further comprising a step of further drying after the solid-liquid separation in step 3) to obtain the compound of formula (I), wherein the drying process comprises drying at room temperature and then drying at a controlled temperature of 30-60 ℃.
11. The method for preparing the compound of formula (I) according to claim 8, further comprising a step of further drying after the solid-liquid separation in step 3) to obtain the compound of formula (I), wherein the drying process comprises drying at room temperature, and then drying at a controlled temperature of 35-45 ℃.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| CN2019113236744 | 2019-12-19 | ||
| CN201911323674 | 2019-12-19 | ||
| PCT/CN2020/136812 WO2021121270A1 (en) | 2019-12-19 | 2020-12-16 | Method for purifying sglts inhibitor and application thereof |
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